Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells

• Published in: Ai zheng Vol. 31; no. 2; pp. 110 - 118
• Main Authors: Peng, Xing-Xiang, Tiwari, Amit K, Wu, Hsiang-Chun, Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: England Department of Pharmacology and Systems Therapeutics, Mount SinaiSchool of Medicine, New York, NY 10029, USA%Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens,NY 11439, USA 01.02.2012; Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens,NY 11439, USA; Department of Psychiatry and Pharmacology, New York University,School of Medicine, 550 First Avenue, New York, NY 10016, USA%Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens,NY 11439, USA; Sun Yat-sen University Cancer Center
• Subjects: Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; Benzamides; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - antagonists & inhibitors; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate; K562 Cells; K562细胞; Mercaptopurine - metabolism; Methotrexate - metabolism; Original; P-糖蛋白; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrimidines - pharmacology; RNA, Messenger - metabolism; 多药耐药; 慢性粒细胞白血病; 白血病细胞; 诱导; 过度表达; 酪氨酸激酶抑制剂; P-glycoprotein; drug transporters; multidrug resistance; imatinib; Human chronic myelogenous leukemia
• ISSN: 1000-467X; 1944-446X
• DOI: 10.5732/cjc.011.10327

Imatinib, a breakpoint cluster region （BCR）-Abelson murine leukemia （ABL） tyrosine kinase inhibitor （TKI）, has revolutionized the treatment of chronic myelogenous leukemia （CML）. However, development of multidrug resistance（MDR） limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line （K562-imatinib） through a stepwise selection process. While characterizing the phenotype of these cells, we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells. In addition, these cells were cross-resistant to second- and third-generation BCR-ABL TKIs. Western blot analysis and reverse transcription-polymerase chain reaction（RT-PCR） demonstrated that P-glycoprotein （P-gp） and MDR1 mRNA levels were increased in K562-imatinib cells. In addition, accumulation of [14C]6-mercaptopurine （6-MP） was decreased, whereas the ATP-dependent efflux of [14C] 6-MP and [3H]methotrexate transport were increased in K562-imatinib cells. These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.